One of the major problems slowing development and regulatory approval of new and safer medical products is the lack of experimental in vitro model systems that can replace costly and time-consuming animal studies by predicting drug efficacy, bioavailability and toxicity in man. Although considerable advances have been made in the development of cell culture models, these methods fail to reconstitute structural and mechanical features of whole living organs and integrated multi-organ system physiology that are central to their function. This project is based on recent breakthroughs in the laboratories ofthe PI and Co-PI that make it possible to engineer biomimetic microsystems technologies that use living human cells cultured within three- dimensional microfluidic systems to replicate the complex physiological functions and mechanical microenvironment ofthe breathing lung and beating heart. The long-term goal of this project is to intejgrate these 'organ-on-chip'microdevices to produce a 'Heart-Lung Micromachine'that can provide quantitative real-time measures of the efficacy, bioavailability and safety of aerosol-based drugs, nanotherapeutics and other medical products on integrated lung and heart function. The specific aims of this proposal include: 1) to demonstrate the ability ofthe breathing lung-on-a-chip device to measure pulmonary absorption, efficacy and toxicity of aerosol-based drugs and nanotherapeutics, 2) to demonstrate the ability ofthe beating heart microdevlce to detect cardiotoxicity by measuring changes in cardiac cell contractility, electrical conduction, and tissue inflammation, and 3) to create an integrated heart-lung microsystem technology that can assess the effects of drugs and nanotherapeutics delivered to the lung by aerosol on cardiac function and toxicity in vitro. In these studies, we will demonstrate proof-of-principle for a new biomimetic microsystem technology that can analyze efficacy and bioavailability, as well as detect adverse toxicities, associated with use of therapeutic agents before entering clinical trials. If successful, these organ-on-chip microdevices could greatly shorten the timeline and reduce costs associated with development of aerosolized drugs, nanotherapies and other medical products, as well as inform regulatory decision-making in the future. PUBLIC HEALTH RELEVANCE: We propose to build a 'Heart-Lung Micromachine'composed of microfluidic channels lined by living cells as a screening platform that could replace animal assays currently used for development and regulatory review of drugs and nanotherapies. This biomimetic technology could greatly shorten the time required to bring drugs to patients, increase their safety, decrease their costs, and improve clinical outcome.